Project Summary Despite decades of effort to reduce HIV transmission, 35 million individuals are still presently infected globally. While the advent of highly active antiretroviral therapy (HAART) against human immunodeficiency virus type 1 (HIV-1) infection has enabled the control and suppression of infection, a large fraction of people worldwide do not currently receive these drugs, resulting in millions of preventable deaths. Those with access to HAART treatment still have persistent infection requiring lifelong adherence to antiviral therapy for viremic suppression and there exists the constant threat of emerging viral resistance. This necessitates continuing investigation into new therapeutics against HIV-1. Isolation of potent broadly neutralizing monoclonal antibodies (bnAbs) that can control infection in humans up to two months after passive transfer has revealed a new potential therapy for HIV-1 infected individuals. In this proposal, I aim to investigate the utilization of `vectored immunoprophylaxis' (VIP), whereby an adeno-associated virus vector is used to deliver systemic monoclonal antibody in vivo, as a novel HIV immunotherapy to effectively control and suppress viral replication. This proposal aims to mimic impending human clinical trials testing vectored bnAbs as immunotherapeutics and will examine the concentration of various AAV-vectored bnAbs required to prevent HIV-1 viral outgrowth in suppressed patient PBMC's in humanized mice. Additionally, BLT humanized mice will be used to examine the ability of combinations of vectored bnAbs to suppress replicating HIV-1, independent of HAART therapy and furthermore, investigate the impact that monoclonal antibody therapy has on the functionality of the immune response in humanized mice. Ultimately, this proposal will predict the success of upcoming clinical trials and efficacy of utilizing a sustained monoclonal antibody expression system as an alternative therapy to HAART.